Sex-specific modulation of amyloid-β on tau phosphorylation underlies faster tangle accumulation in females

著者: Yi‐Ting Wang, Joseph Therriault, Stijn Servaes, Cécile Tissot, Nesrine Rahmouni, Arthur C. Macedo, Jaime Fernández Arias, Sulantha Mathotaarachchi, Andréa Lessa Benedet, Jenna Stevenson, Nicholas J. Ashton, Firoza Z Lussier, Tharick A. Pascoal, Henrik Zetterberg, Maria Natasha Rajah, Kaj Blennow, Serge Gauthier, Pedro Rosa‐Neto, for the Alzheimer’s Disease Neuroimaging Initiative, Michael W Weiner, Paul Aisen, Michael W Weiner, Paul Aisen, Ronald Petersen, Clifford R Jack, William J. Jagust, John Q. Trojanowki, Arthur W Toga, Laurel Beckett, Robert C. Green, Andrew J Saykin, John C. Morris, Richard J Perrin, Leslie M. Shaw, Zaven S. Khachaturian, Maria Carrillo, William Z. Potter, Lisa L. Barnes, Marie Bernard, John K Hsiao, Jonathan Jackson, Eliezer Masliah, Donna Masterman, Ozioma C. Okonkwo, Richard J. Perrin, Laurie Ryan, Nina Silverberg, Adam Fleisher, Michael W Weiner, Diana Truran Sacrey, Juliet Fockler, Cat Conti, Dallas P. Veitch, John Neuhaus, Chengshi Jin, Rachel L. Nosheny, Miriam T. Ashford, Derek Flenniken, Adrienne Kormos, Robert C Green, Tom Montine, Cat Conti, Ronald Petersen, Paul Aisen, Michael S. Rafii, Rema Raman, Gustavo Jiménez, Michael Donohue, Devon Gessert, Jennifer Salazar, Caileigh Zimmerman, Yuliana Cabrera, Sarah Walter, Garrett Miller, Godfrey Coker, Taylor Clanton, Lindsey Hergesheimer, Stephanie Smith, Olusegun Adegoke, Payam Mahboubi, Shelley Moore, Jeremy Pizzola, Elizabeth Shaffer, Brittany Sloan, Laurel Beckett, Danielle Harvey, Michael Donohue, Clifford R Jack, Arvin Forghanian-Arani, Bret Borowski, Chad Ward, Christopher G. Schwarz, David Jones, Jeff Gunter, Kejal Kantarci, Matthew L. Senjem, Prashanthi Vemuri, Robert I. Reid, Nick C. Fox, Ian B. Malone, Paul M. Thompson, Sophia I. Thomopoulos, Talia M. Nir, Neda Jahanshad, Charles DeCarli, Alexander Knaack, Evan Fletcher, Danielle Harvey, Duygu Tosun, Stephanie Rossi Chen, Mark Choe, Karen Crawford, Paul A. Yushkevich, Sandhitsu R. Das, William J. Jagust, Robert A. Koeppe, Eric M Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C. Morris, Richard J. Perrin, Nigel J. Cairns, Erin Householder, Erin Franklin, Haley Bernhardt, Lisa Taylor‐Reinwald, Leslie M. Shaw, John Q. Trojanowki, Magdalena Korecka, Michal Figurski, Arthur W Toga, Scott Neu, Andrew J Saykin, Kwangsik Nho, Shannon L. Risacher, Liana G. Apostolova, Li Shen, Tatiana M Foroud, Kelly Nudelman, Kelley Faber, Kristi Wilmes, Michael W Weiner, Leon J. Thal, Zaven S. Khachaturian, John K Hsiao, Lisa C. Silbert, Betty Lind, Rachel Crissey, Jeffrey Kaye, Raina Carter, Sara Dolen, Joseph Quinn, Lon S Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Karen Dagerman, Bryan M Spann, James B. Brewer, Helen Vanderswag, Adam Fleisher, Jaimie Ziolkowski, Judith L. Heidebrink, Lisa Zbizek-Nulph, Joanne Lord, Lisa Zbizek-Nulph, Ronald Petersen, Sara S. Mason, Colleen S. Albers, David S. Knopman, Kris Johnson, Javier Villanueva-Meyer, Valory Pavlik, Nathaniel Pacini, Ashley Lamb, Joseph S. Kass, Rachelle S. Doody, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Akiva Mintz, Beau M. Ances, John C Morris, David Winkfield, Maria Carroll, Georgia Stobbs-Cucchi, Angela Oliver, Mark A. Mintun, Stacy Schneider, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Daniel Marson, Hillel Grossman, Martin Goldstein, Jonathan Greenberg, Effie Mitsis, Raj C. Shah, Melissa Lamar, Patricia Samuels, Ranjan Duara, Maria T. Greig‐Custo, Rosemarie Rodriguez, Marilyn Albert, Chiadi Onyike, Leonie Farrington, Scott Rudow, Rottislav Brichko, Stephanie Kielb, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Martin Sadowski, Thomas Wısnıewskı, Melanie Shulman, Arline Faustin, Julia Rao, Karen M. Castro, Anaztasia Ulysse, Shannon Chen, Mohammed O. Sheikh, Jamika Singleton-Garvin, P. Murali Doraiswamy, Jeffrey R. Petrella, Olga James, Terence Z. Wong, Salvador Borges‐Neto, Jason Karlawish, David A. Wolk, Sanjeev Vaishnavi, Christopher M. Clark, Steven E. Arnold, Charles D. Smith, Gregory A. Jicha, Riham El Khouli, Flavius D. Raslau, Oscar L. López, MaryAnn Oakley, Donna M Simpson, Anton P. Porsteinsson, Kim Martin, Nancy Kowalski, Melanie Keltz, Bonnie S. Goldstein, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Gaby Thai, Aimee Pierce, Beatriz Yanez, Elizabeth Sosa, Megan Witbracht, Brendan Kelley, Trung Nguyen, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I. Levey, James J. Lah, Ihab Hajjar, Janet S. Cellar, Jeffrey M. Burns, Russell H. Swerdlow, William M. Brooks, H S Daniel Silverman, Sarah Kremen, Liana G. Apostolova, Kathleen Tingus, Po H. Lu, George Bartzokis, Ellen Woo, Edmond Teng, Neill R. Graff‐Radford, Francine Parfitt, Kim Poki-Walker, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, Christopher H. van Dyck, Adam P. Mecca, Adam P Mecca, Susan P. Good, Martha G. MacAvoy, Richard E. Carson, Pradeep Varma, Howard Chertkow, Susan Vaitekunis, Chris Hosein, Sandra E. Black, Bojana Stefanovic, Chris Heyn, Ging‐Yuek Robin Hsiung, Ellen Kim, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternak, Irina Rachinsky, Andrew Kertesz, Dick Drost, John Rogers, Ian Grant, Brittanie Muse, Emily Rogalskı, Jordan Robson, M-Marsel Mesulam, Diana Kerwin, Chuang‐Kuo Wu, Nancy E. Johnson, Kristine Lipowski, Sandra Weıntraub, Borna Bonakdarpour, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Howard J. Rosen, Bruce L. Miller, David C. Perry, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Kelly McCann, Jessica Poe, Reisa A. Sperling, Keith A. Johnson, Gad A. Marshall, Jerome A. Yesavage, Joy L. Taylor, Steven Chao, Jaila Coleman, Jessica D. White, Barton Lane, Allyson Rosen, Jared Tinklenberg, Christine M Belden, Alireza Atri, Bryan M. Spann, Kelly Clark, Edward Zamrini, Marwan Sabbagh, Ronald Killiany, Robert A. Stern, Jesse Mez, Neil W. Kowall, Andrew E. Budson, Thomas O Obisesan, Oyonumo Ntekim, Saba Wolday, Javed Khan, Evaristus Nwulia, Sheeba Nadarajah, Alan J. Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli, Owen Carmichael, Vernice Bates, Horacio Capote, Michelle Rainka, Michael Borrie, T‐Y Lee, Robert Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Allison Perrin, Anna Burke, Douglas W. Scharre, Maria Kataki, Rawan Tarawneh, Brendan Kelley, David Hart, Earl A. Zimmerman, Dzintra Celmins, Del D. Miller, Laura L. Boles Ponto, Karen Ekstam Smith, Hristina Koleva, Hyungsub Shim, Ki Won Nam, Susan K. Schultz, Jeff D. Williamson, Suzanne Craft, Jo Cleveland, Mia Yang, Kaycee M. Sink, Brian R. Ott, Jonathan Drake, Geoffrey Tremont, Lori A. Daiello, Jonathan Drake, Marwan Sabbagh, Aaron Ritter, Charles Bernick, Donna Munic, Akiva Mintz, Abigail O’Connelll, Jacobo Mintzer, Arthur Wiliams, Joseph C. Masdeu, Jiong Shi, Angelica Garcia, Marwan Sabbagh, Paul Newhouse, Steven G. Potkin, Stephen Salloway, Paul Malloy, Stephen Correia, Smita Kittur, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Laura A. Flashman, Marc Seltzer, Mary L. Hynes, Robert B. Santulli, Norman Relkin, Gloria Chiang, Michael Lin, Lisa Ravdin, Athena Lee, Michael W Weiner, Paul Aisen, Michael W Weiner, Paul Aisen, Ronald Petersen, Robert C. Green, Danielle Harvey, Clifford R Jack, William J. Jagust, John C Morris, Andrew J Saykin, Leslie M Shaw, Arthur W Toga, John Q. Trojanowki, Thomas C. Neylan, Jordan Grafman, Robert C. Green, Tom Montine, Michael W Weiner, Ronald Petersen, Paul Aisen, Gustavo Jiménez, Michael Donohue, Devon Gessert, Jennifer Salazar, Caileigh Zimmerman, Sarah Walter, Olusegun Adegoke, Payam Mahboubi, Sarah Danowski, Godfrey Coker, Taylor Clanton, Jeremy Pizzola, Elizabeth Shaffer, Catherine Nguyen-Barrera, Thomas C. Neylan, Jacqueline Hayes, Shannon Finley, Danielle Harvey, Michael Donohue, Clifford R Jack, Matt A. Bernstein, Bret Borowski, Jeff Gunter, Matthew L. Senjem, Kejal Kantarci, Chad Ward, Stephanie Rossi Chen, Susan Landau, Robert A. Koeppe, Norm Foster, Eric M Reiman, Kewei Chen, John C. Morris, Richard J Perrin, Erin Franklin, Leslie M. Shaw, John Q Trojanowki, Magdalena Korecka, Michal Figurski, Arthur W Toga, Karen Crawford, Scott Neu, Andrew J Saykin, Tatiana M Foroud, Steven G. Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Kristi Wilmes, Lon S Schneider, Liberty Teodoro, Karen Dagerman, Bryan M Spann, James B. Brewer, Helen Vanderswag, Adam Fleisher, Yaakov Stern, Lawrence S. Honig, Akiva Mintz, Raj C. Shah, Ajay Sood, Kimberly S. Blanchard, Ranjan Duara, Daniel Varon, Maria T. Greig, P. Murali Doraiswamy, Salvador Borges‐Neto, Terence Z. Wong, Anton P. Porsteinsson, Gaby Thai, Aimee Pierce, Christopher Reist, Beatriz Yanez, Elizabeth Sosa, Megan Witbracht, Carl Sadowsky, Walter Martínez, Teresa Villena, Howard J. Rosen, David C. Perry, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Kelly McCann, Jessica Poe, Reisa A. Sperling, Keith A. Johnson, Gad A. Marshall, Christine M Belden, Alireza Atri, Bryan M. Spann, Kelly Clark, Edward Zamrini, Marwan Sabbagh, Thomas O Obisesan, Oyonumo Ntekim, Saba Wolday, Evaristus Nwulia, Sheeba Nadarajah, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome A. Yesavage, Joy L. Taylor, Steven Chao, Jaila Coleman, Jessica D. White, Barton Lane, Allyson Rosen, Jared Tinklenberg, Michael Lin, Gloria Chiang, Lisa Ravdin, Norman Relkin, Abigail O’Connelll, Jacobo Mintzer, Arthur Wiliams, Scott Mackin, Paul Aisen, Rema Raman, Gustavo Jimenez‐Maggiora, Michael Donohue, Devon Gessert, Jennifer Salazar, Caileigh Zimmerman, Sarah Walter, Olusegun Adegoke, Payam Mahboubi, Scott Mackin, Michael W Weiner, Paul Aisen, Rema Raman, Clifford R Jack, Susan Landau, Andrew J Saykin, Arthur W Toga, Charles DeCarli, Robert A. Koeppe, Robert C Green, Erin Drake, Michael W Weiner, Paul Aisen, Rema Raman, Mike Donohue, Scott Mackin, Craig Nelson, David Bickford, Meryl A. Butters, Michelle Zmuda, Clifford R Jack, Matt A. Bernstein, Bret Borowski, Jeff Gunter, Matthew L. Senjem, Kejal Kantarci, Chad Ward, Denise A. Reyes, Robert A. Koeppe, Susan Landau, Arthur W Toga, Scott Neu, Andrew J Saykin, Tatiana Foroud, Kelley Faber, Kwangsik Nho, Kelly Nudelman, Scott Mackin, Howard J. Rosen, Craig Nelson, David Bickford, Yiu Ho Au, Kelly Scherer, Daniel Catalinotto, Samuel Stark, Elise Ong, Dariella Fernandez, Meryl A. Butters, Michelle Zmuda, Oscar L. López, MaryAnn Oakley, Donna M Simpson - Brain 2023 被引用: 42

Females are disproportionately affected by dementia due to Alzheimer's disease. Despite a similar amyloid-β (Aβ) load, a higher load of neurofibrillary tangles (NFTs) is seen in females than males. Previous literature has proposed that Aβ and phosphorylated-tau (p-tau) synergism accelerates tau tangle formation, yet the effect of biological sex in this process has been overlooked. In this observational study, we examined longitudinal neuroimaging data from the TRIAD and ADNI cohorts from Canada and USA, respectively. We assessed 457 participants across the clinical spectrum of Alzheimer's disease. All participants underwent baseline multimodal imaging assessment, including MRI and PET, with radioligands targeting Aβ plaques and tau tangles, respectively. CSF data were also collected. Follow-up imaging assessments were conducted at 1- and 2-year intervals for the TRIAD cohort and 1-, 2- and 4-year intervals for the ADNI cohort. The upstream pathological events contributing to faster tau progression in females were investigated-specifically, whether the contribution of Aβ and p-tau synergism to accelerated tau tangle formation is modulated by biological sex. We hypothesized that cortical Aβ predisposes tau phosphorylation and tangle accumulation in a sex-specific manner. Findings revealed that Aβ-positive females presented higher CSF p-tau181 concentrations compared with Aβ-positive males in both the TRIAD (P = 0.04, Cohen's d = 0.51) and ADNI (P = 0.027, Cohen's d = 0.41) cohorts. In addition, Aβ-positive females presented faster NFT accumulation compared with their male counterparts (TRIAD: P = 0.026, Cohen's d = 0.52; ADNI: P = 0.049, Cohen's d = 1.14). Finally, the triple interaction between female sex, Aβ and CSF p-tau181 was revealed as a significant predictor of accelerated tau accumulation at the 2-year follow-up visit (Braak I: P = 0.0067, t = 2.81; Braak III: P = 0.017, t = 2.45; Braak IV: P = 0.002, t = 3.17; Braak V: P = 0.006, t = 2.88; Braak VI: P = 0.0049, t = 2.93). Overall, we report sex-specific modulation of cortical Aβ in tau phosphorylation, consequently facilitating faster NFT progression in female individuals over time. This presents important clinical implications and suggests that early intervention that targets Aβ plaques and tau phosphorylation may be a promising therapeutic strategy in females to prevent the further accumulation and spread of tau aggregates.